This invention generally pertains to the fields of medicine and cancer therapeutics. In particular, this invention provides compositions and methods for detecting changes in rates of water diffusion in a tissue of an individual. Thus; the invention also provides a non-invasive means to evaluate the effectiveness of a therapy for a disorder of cell growth, such as cancer.
Primary brain tumors account for more than 26% of childhood and 2% of adult cancer deaths in the United States. Sadly, improvements in five-year survival rates for brain tumor patients have been rather modest over the past 20 years despite significant advances in stereotactic neurosurgery and focal conformal radiation therapy. Progress in adjuvant chemotherapy has also been disappointing, with few demonstrable gains made since the initial trials of alkylnitrosoureas (e.g., BCNU) in 1978. The failure of new chemotherapeutic regimens to improve patient survival may be because less than 50% of tumors will respond to a given protocol. Adjuvant chemotherapy may be made more successful if the responsiveness of a tumor to a given protocol could be assessed in a more timely fashion than currently available, thereby, allowing trials of multiple regimens.
Currently, weeks to months pass before an evaluation of the effectiveness of a therapy for a CNS tumors is made. This evaluation involves examining changes in the maximal cross sectional area of a CNS tumor or the product of the maximal perpendicular tumor diameter. This involves comparison of sequential MRI scans; see, e.g., Buckner (1995) J. Neurosurg. 82:430-435; Grossman (1988) Semin. Oncol. 15:441-454; Vinitski (1988) J. Magn. Reson. Imaging 8:814-819; Watling (1994) J. Clin. Oncol. 12:1886-1889; James (1999) J. Natl. Cancer Inst. 91:523-528. Gadolinium-enhanced T1-weighted images are often used. T2-weighting or other MR contrast strategies are also employed. Comparisons of tumor burden are usually made between pre-treatment scans and those obtained weeks to months following the conclusion of a therapeutic protocol; see, e.g., Therasse (2000) J. Natl. Cancer Inst. 92:205-216.
Methods of assessing treatment responses that are not dependent on relatively slow changes in tumor volume may be capable of providing earlier indications of therapeutic outcome. In pursuit of this goal, attempts have been made to correlate changes in brain tumor biochemistry with therapeutic response using MR spectroscopy (see, e.g., Kurhanewicz (2000) Neoplasia 2:166-189; Ross, et al., xe2x80x9cIn vivo magnetic resonance imaging and spectroscopy: Application to brain tumors. In Magnetic Resonance Spectroscopy and Imaging in Neurochemistry;xe2x80x9d Bachelard H, ed. New York: Plenum Press, 1997, pp 145-178) and [18F]fluorodeoxyglucose PET imaging (see, e.g., Brock (2000) Br. J. Cancer 82:608-615.
The invention provides a computer-implemented method for detecting changes in rates of water diffusion in a tissue. The method can be practiced in vitro, ex vivo or in vivo, as, in an individual. The method comprises the following steps: (a) providing a magnetic resonance imaging (MRI) device capable of outputting data to a computer; (b) providing a computer capable of storing and analyzing data input from the MRI device comprising a computer program product embodied therein; (c) projecting a sequence of magnetic field gradient pulses and radiofrequency pulses to the tissue of interest by the MRI device and collecting a first set of MRI signals from the tissue and outputting this data to the computer, wherein the MRI device collects MRI signals from the tissue of interest at multiple diffusion sensitivities and diffusion directions; (d) analyzing the first set of diffusion-sensitive MRI signal readings by the computer program product to calculate an apparent diffusion coefficient (ADC) value for each diffusion direction, wherein an ADC value corresponds to a spatial origin of the signals used to determine the ADC value, and to generate a first spatial map of ADC values; (e) projecting at least a second sequence of magnetic field gradient pulses and radiofrequency pulses and analyzing at least a second set of diffusion-sensitive MRI readings in the same tissue of interest as in steps (c) and (d) to generate at least a second subsequent spatial map of ADC values; and (f) compare the first and subsequent spatial maps of ADC values to generate a spatial map that reflects the changes in ADC values over the time the several readings were taken by the MRI, wherein the changes in ADC values reflect the changes in spin diffusion properties which reflect changes in rates of water diffusion in the tissue.
In one embodiment of the computer-implemented method of the invention, the computer program product uses the spatial map that reflects the changes in ADC values over the time the several readings were taken by the MRI to generate a histogram (see Example 1, below, for examples of histograms).
In one embodiment, an increase in the rate of water diffusion as shown by the spatial map that reflects the changes in ADC values over the time taken by the MRI indicates cell damage or tissue microvasculature damage. A rate of water diffusion higher or lower than considered normal for the tissue of interest can indicate cell damage or tissue microvasculature damage.
In alternative embodiments, tissue or body section of interest imaged by the methods of the invention is brain or spinal cord tissue, an internal organ, a skeletal and a muscle tissue. The tissue or body section of interest imaged by the methods of the invention can be normal, injured or inflamed tissue or diseased tissue; or, tissues in the process of aided or unaided treatment or therapy. For example, the diseased tissue can be a cancer, such as a solid tumor. The tissue can have been exposed to a drug, a biological agent, hyperthermia, hypothermia, a radiation or a combination thereof. The tissue can have been exposed to an antivascular therapy. In one embodiment, the radiation is a radiotherapy or a photodynamic therapy or a combination thereof.
In alternative embodiments, the computer-implemented method of the invention can determine the effectiveness of an organ or a tissue transplant or a therapy for a condition or a disease or an injury. For example, the therapy can be for a cancer, such as a sold tumor. An increase in diffusion indicates tumor cell damage or tumor microvasculature damage, thereby indicating the effectiveness of the therapy. In another embodiment, a change in diffusion indicates tissue repair. For example, the therapy can be for an injured or inflamed tissue and a charge in diffusion indicates tissue repair or decreased inflammation, thereby indicating the effectiveness of the therapy.
In one embodiment, the ADC values from a defined spatial subsection of the tissue taken over time is used to generate a statistical data reduction of data in that spatial subsection. The statistical data reduction can comprise a mean, a standard deviation, a pixel count or a volume of tissue or a combination thereof.
In one embodiment, the computer-implemented method generates a histogram from the statistical data reduction. The histogram can reflect changes in statistical data reduction sets over time.
In one embodiment, a first set of diffusion-sensitive MRI signal readings is generated before initiation of a therapy. Subsequent sets of diffusion-sensitive MRI signal readings can be generated after initiation of a therapy. A subsequent set of diffusion-sensitive MRI signal readings can be generated at a time appropriate for a therapeutic change to be apparent in tissue. If therapeutic changes in tissue as quantified by the methods of the invention via diffusion MRI are insufficient, a change in therapy may be indicated, e.g., in the treatment of a tumor, a change from radiotherapy to chemotherapy, or, vise versa.
The invention also provides a computer program product for use in the detection of changes in rates of water diffusion in a tissue using magnetic resonance imaging (MRI) comprising a computer useable medium comprising a computer readable program code embodied therein, wherein the computer program product is capable of storing and analyzing data input from a MIM device by a process comprising the following steps: (a) providing a magnetic resonance imaging (MRI) device capable of outputting data to a computer; (b) providing a computer capable of storing and analyzing data input from the MRI device comprising a computer program product embodied therein; (c) projecting a sequence of magnetic field gradient pulses and radio-frequency pulses to the tissue of interest by the MRI device and collecting a first set of MRI signals from the tissue and outputting this data to the computer, wherein the MRI device collects MRI signals from the tissue of interest at multiple diffusion sensitivities and diffusion directions; (d) analyzing the first set of diffusion-sensitive MRI signal readings by the computer program product to calculate an apparent diffusion coefficient (ADC) value for each diffusion direction, wherein an ADC value corresponds to a spatial origin of the signals used to determine the ADC value, and to generate a first spatial map of ADC values; (e) projecting at least a second sequence of magnetic field gradient pulses and radio-frequency pulses and analyzing at least a second set of diffusion-sensitive MRI readings in the same tissue of interest as in steps (c) and (d) to generate at least a second subsequent spatial map of ADC values; and, (f) compare the first and subsequent spatial maps of ADC values to generate a spatial map that reflects the changes in ADC values over the time the several readings were taken by the MRI, wherein the changes in ADC values reflect the changes in spin diffusion properties which reflect changes in rates of water diffusion in the tissue.
The invention also provides a computer system, comprising a processor and a computer program product of the invention. The invention also provides a tissue imaging system, comprising: (a) a magnetic resonance imaging (MRI) device capable of outputting data to a processor; (b) a processor; and, (c) a computer program product of the invention embodied within the processor.
The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.
All publications, patents, patent applications, GenBank sequences and ATCC deposits, cited herein are hereby expressly incorporated by reference for all purposes.